US2022133722A1PendingUtilityA1

Pharmaceutical compositions

46
Assignee: QUE Oncology Pty LtdPriority: Feb 15, 2019Filed: Feb 14, 2020Published: May 5, 2022
Est. expiryFeb 15, 2039(~12.6 yrs left)· nominal 20-yr term from priority
A61P 5/00A61J 1/035A61K 31/506A61K 9/0053A61K 9/2806A61K 9/2004A61K 9/08A61K 9/2086A61P 5/24A61K 9/48A61K 9/12A61K 9/0095A61K 9/4841A61K 9/10
46
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Claims

Abstract

The present invention relates to pharmaceutical compositions for the treatment or prevention of symptoms associated with endocrine disturbances, such as hot flashes. The pharmaceutical compositions comprise a tricyclic amino containing compound of formula (I), such as MSX-122 (also known as “Q-122”) (N,N′-(1,4-phenylenebis(methylene))bis(pyrimidin-2-amine)), and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be given in certain doses and/or dosing regimens, preferably twice daily.

Claims

exact text as granted — not AI-modified
1 . A method of treating or preventing a symptom associated with an endocrine disturbance in a subject in need thereof, the method comprising administering twice daily to the subject an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R. 
       
     
     
         2 . Use of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       in the manufacture of a medicament for treating or preventing a symptom associated with an endocrine disturbance, wherein the medicament is formulated for twice daily administration of the compound or pharmaceutically acceptable salt or prodrug thereof. 
     
     
         3 . Use of an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       for the treatment or prevention of a symptom associated with an endocrine disturbance in a subject, wherein the effective amount is for twice daily administration of the pharmaceutical composition. 
     
     
         4 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       and one or more pharmaceutically acceptable excipients, for use in the treatment or prevention of a symptom associated with an endocrine disturbance in a subject, wherein the treatment or prevention comprises twice daily administration of the compound. 
     
     
         5 . A pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       and one or more pharmaceutically acceptable excipients, for use in the treatment or prevention of a symptom associated with an endocrine disturbance in a subject, wherein the treatment or prevention comprises twice daily administration of the pharmaceutical composition. 
     
     
         6 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  5 , wherein the compound or the pharmaceutical composition is administered with a consumable. 
     
     
         7 . The method, use, compound or pharmaceutical composition according to  claim 6 , wherein the consumable is a high-fat consumable. 
     
     
         8 . The method, use, compound or pharmaceutical composition according to  claim 7 , wherein the high-fat consumable a high-fat food or meal, or an edible fat or oil. 
     
     
         9 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  8 , wherein the compound or the pharmaceutical composition is administered to the subject in an amount of between about 50 mg and about 400 mg per dose. 
     
     
         10 . The method, use, compound or pharmaceutical composition according to  claim 9 , wherein the amount is between about 60 mg and about 350 mg per dose. 
     
     
         11 . The method, use, compound or pharmaceutical composition according to  claim 10 , wherein the amount is about 100 mg per dose. 
     
     
         12 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  11 , wherein the symptom is a hot flash. 
     
     
         13 . A method of treating or preventing hot flashes in a subject, the method comprising administering an effective amount a compound of formula (I) or an effective amount a pharmaceutical composition comprising formula (I): comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       and one or more pharmaceutically acceptable excipients, in an amount and at an interval of 100 mg of compound of formula (I) twice every 24 hours. 
     
     
         14 . The method of  claim 12 , wherein 100 mg of the compound is administered once every 12 hours. 
     
     
         15 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  14 , wherein Q, T, U, and V are independently selected from H or methyl. 
     
     
         16 . The method, use, compound or pharmaceutical composition according to  claim 15 , wherein Q, T, U, and V are H. 
     
     
         17 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  16 , wherein W, X, Y and Z are independently selected from H, R, F, Cl, OH, OR or CO 2 H. 
     
     
         18 . The method, use, compound or pharmaceutical composition according to  claim 17 , wherein W, X, Y and Z are independently selected from H, R, F, Cl, OR or CO 2 H. 
     
     
         19 . The method, use, compound or pharmaceutical composition according to  claim 18 , wherein W, X, Y and Z are independently selected from H, R, F, Cl or OR. 
     
     
         20 . The method, use, compound or pharmaceutical composition according to  claim 19 , wherein each of W, X, Y and Z is H. 
     
     
         21 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  20 , wherein R 1  and R 2  are independently selected from H. 
     
     
         22 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  21 , wherein R 3 , R 4 , R 5  and R 6  are independently selected from H. 
     
     
         23 . The method, use, compound or pharmaceutical composition according to any one of  claims 1  to  22 , wherein the compound is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         24 . A unit dosage form comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
         and one or more pharmaceutically acceptable excipients, 
         wherein the unit dosage form comprises the compound of formula (I) or pharmaceutically acceptable salt or prodrug thereof in an amount sufficient for twice daily administration to a subject in need thereof. 
       
     
     
         25 . The unit dosage form according to  claim 24 , comprising from about 60 mg to about 400 mg of the compound of formula (I) or pharmaceutically acceptable salt or prodrug thereof. 
     
     
         26 . The unit dosage form according to  claim 24  or  25 , comprising about 100 mg of the compound of formula (I) or pharmaceutically acceptable salt or prodrug thereof. 
     
     
         27 . The unit dosage form according to any one of  claims 24  to  26 , formulated for oral administration. 
     
     
         28 . A kit comprising in separate compartments,
 a first unit dosage form according to any one of  claims 24  to  27 ;   a second unit dosage form according to any one of  claims 24  to  27 ,   wherein the kit is adapted to allow access to each compartment at a different time.   
     
     
         29 . The kit of  claim 28 , wherein the first and second unit dosage form comprise the same amount of the compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         30 . The kit of  claim 28  or  29 , further comprising indicia distinguishing the first and second unit dosage forms from each other. 
     
     
         31 . The kit of any one of  claims 28  to  30 , comprising a plurality of first unit dosage forms and a plurality of second unit dosage forms, each unit dosage forms within either plurality contained in a separate container adapted for to allow access at different times. 
     
     
         32 . The kit according to any one of  claims 28  to  31 , wherein the first and second unit dosage form is provided in the form of a tablet. 
     
     
         33 . The kit according to any one of  claims 28  to  32 , wherein the containers are provided in the form of a blister pack. 
     
     
         34 . The kit of any one of  claims 28  to  31 , further comprising instructions for coordinating the administration of the first and second dosage units as part of a treatment or prevention regimen comprising separate administration of a first unit dosage form and a second unit dosage form within a 24 hour period. 
     
     
         35 . The kit according to  claim 34 , wherein the instructions coordinate the subject to take the first and second unit dosage forms with a high fat consumable. 
     
     
         36 . A method of treating or preventing a symptom associated with an endocrine disturbance in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
         in combination with, or at the same time as, consumption of a high-fat consumable. 
       
     
     
         37 . The method of  claim 36 , wherein the compound is administered once every 24 hours. 
     
     
         38 . The method of  claim 36 , wherein the compound is administered twice every 24 hours. 
     
     
         39 . The method of any one of  claims 36  to  38 , wherein the high-fat consumable a high-fat food or meal, or an edible fat or oil. 
     
     
         40 . The method according to any one of  claims 36  to  39 , wherein the compound is administered to the subject in an amount of between about 50 mg and about 400 mg per dose. 
     
     
         41 . The method according to any one of  claims 36  to  40 , wherein the amount is between about 60 mg and about 350 mg per dose. 
     
     
         42 . The method according to any one of  claims 36  to  41 , wherein the amount is about 100 mg per dose. 
     
     
         43 . The method according to any one of  claims 36  to  42 , wherein the symptom is a hot flash. 
     
     
         44 . The method according to any one of  claims 36  to  43 , wherein Q, T, U, and V are independently selected from H or methyl. 
     
     
         45 . The method according to  claim 44 , wherein Q, T, U, and V are H. 
     
     
         46 . The method according to any one of  claims 36  to  45 , wherein W, X, Y and Z are independently selected from H, R, F, Cl, OH, OR or CO 2 H. 
     
     
         47 . The method according to  claim 46 , wherein W, X, Y and Z are independently selected from H, R, F, Cl, OR or CO 2 H. 
     
     
         48 . The method according to  claim 47 , wherein W, X, Y and Z are independently selected from H, R, F, Cl or OR. 
     
     
         49 . The method according to  claim 48 , wherein each of W, X, Y and Z is H. 
     
     
         50 . The method according to any one of  claims 36  to  49 , wherein R 1  and R 2  are independently selected from H. 
     
     
         51 . The method according to any one of  claims 36  to  50 , wherein R 3 , R 4 , R 5  and R 6  are independently selected from H. 
     
     
         52 . The method according to any one of  claims 36  to  51 , wherein the compound is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         53 . Use of an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         each K is independently N or CH, wherein at least two K's are N; 
         Q, T, U, and V are independently selected from H or R; 
         W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO 2 H; 
         R is an alkyl group; 
         R 1  and R 2  are independently selected from H or R, and 
         R 3 , R 4 , R 5  and R 6  are independently selected from H or R, 
       
       in the manufacture of a medicament for the treatment or prevention of a symptom associated with an endocrine disturbance in a subject, wherein the medicament is for administration with the consumption of a high-fat consumable. 
     
     
         54 . The use according to  claim 53 , wherein the compound is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof.

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